Abstract
The application of dermal papilla cells to hair follicle (HF) regeneration has attracted a great deal of attention. However, cultured dermal papilla cells (DPCs) tend to lose their capacity to induce hair growth during passage, restricting their usefulness. Accumulating evidence indicates that DPCs regulate HF growth mainly through their unique paracrine properties, raising the possibility of therapies based on extracellular vesicles (EVs). In this study, we explored the effects of EVs from high- and low-passage human scalp follicle dermal papilla cells (DP-EVs) on activation of hair growth, and investigated the underlying mechanism. DP-EVs were isolated by ultracentrifugation and cultured with human scalp follicles, hair matrix cells (MxCs), and outer root sheath cells (ORSCs), and we found low-passage DP-EVs accelerated HF elongation and cell proliferation activation. High-throughput miRNA sequencing and bioinformatics analysis identified 100 miRNAs that were differentially expressed between low- (P3) and high- (P8) passage DP-EVs. GO and KEGG pathway analysis of 1803 overlapping target genes revealed significant enrichment in the BMP/TGF-β signaling pathways. BMP2 was identified as a hub of the overlapping genes. miR-140-5p, which was highly enriched in low-passage DP-EVs, was identified as a potential regulator of BMP2. Direct repression of BMP2 by miR-140-5p was confirmed by dual-luciferase reporter assay. Moreover, overexpression and inhibition of miR-140-5p in DP-EVs suppressed and increased expression of BMP signaling components, respectively, indicating that this miRNA plays a critical role in hair growth and cell proliferation. DP-EVs transport miR-140-5p from DPCs to epithelial cells, where it downregulates BMP2. Therefore, DPC-derived vesicular miR-140-5p represents a therapeutic target for alopecia.
Highlights
Hair loss is a widespread and progressive disorder that plagues a large number of people
The results revealed that hair follicle (HF) treated with dermal papilla (DP)-extracellular vesicles (EVs) (P3) had the most Ki67-positive cells in lower outer root sheath (ORS) and hair matrix (p < 0.01) (Figures 2G,H), indicating that HFs treated with low-passage dermal papilla-derived extracellular vesicle (DP-EV) significantly activated hair growth
It is well established that dermal papilla cell (DPC) induce HF morphogenesis (Biernaskie et al, 2009; Ojeh et al, 2015; Owczarczyk-Saczonek et al, 2018): when mixed with infantile keratinocytes in a specific proportion, implanted DPCs can induce the growth of new HFs in rodents (Amici et al, 2009), and experiments in immunedeficient rats have shown that cells derived from the DP can be incorporated into existing DPs, giving rise to stronger HFs (Biernaskie et al, 2009)
Summary
Hair loss is a widespread and progressive disorder that plagues a large number of people. HF morphogenesis and cycling are regulated by complex and intricate interactions between the epithelial and mesenchymal cells, and require spatiotemporal integration of multiple stimulatory and inhibitory signals (Kishimoto et al, 2000; Baker and Murray, 2012; Veraitch et al, 2013; Kandyba and Kobielak, 2014) In this process, the dermal papilla (DP), a unique stem cell niche derived from the mesenchyme, serves as the signaling center that triggers hair cycling through a paracrine signaling mechanism (Inui and Itami, 2011; Leiros et al, 2012; Zhang et al, 2014). EVs secreted from DPCs can accelerate hair growth in vivo and in vitro (Zhou et al, 2018; Yan et al, 2019; Kwack et al, 2019; le Riche et al, 2019), but the mechanisms underlying this growth-promoting effect remain to be fully elucidated
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